Long-term voluntary running prevents the onset of symptomatic Friedreich’s ataxia in mice

Abstract

the common clinical symptoms of Friedreich's ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia in the Caucasian population 1-4 with detrimental clinical symptoms, including ataxia, muscle weakness, type 2 diabetes and heart failure 5,6 . These symptoms usually first appear in childhood or adolescence and worsen over time. A hypertrophic cardiomyopathy is an important clinical trait, which contributes significantly to disability and early death 7,8 . A high percentage of FRDA patients have glucose intolerance or diabetes mellitus 4 , and exercise capacity is usually severely diminished 9 , leading to wheelchair binding within 10 to 20 years after the disease onset 10 .FRDA is caused by GAA repeat expansions in both alleles of the frataxin (FXN) gene within intron 1 located in chromosome 9 11,12 from normally around 5-30 to >90 6,12 . The GAA expansion mutations lead to reduced expression of frataxin, a mitochondrial protein, which is involved in assembly of iron-sulfur clusters (ISC) and/or function as an iron chaperone or an iron storage protein 13 . Although the precise function of frataxin is not entirely clear yet, substantial evidence shows that frataxin deficiency leads to inefficient use of iron during ISC synthesis, inhibition of ISC formation and/or increased production of reactive oxygen species (ROS) via the Fenton reaction, resulting in iron deposition, mitochondrial dysfunction and oxidative damage 14,15 . It is these abnormal functions in the metabolically active tissues/organs that eventually lead to the onset of clinical symptoms. Unfortunately, no pharmacologic treatment up to date has been proven to impede FRDA progression ...

Frataxin controls ketone body metabolism through regulation of OXCT1

“…As prolonged exercise stimulates the capacity of skeletal muscle to take up ketones from blood ( 29 ), OXCT1 reduction in the skeletal muscle of FRDA patients could contribute to prolonged postexercise recovery and exercise intolerance ( 11 , 12 , 30 , 31 ), a significant clinical feature of early FRDA. Exercise intolerance in KIKO mice (at as early as 6 months of age) occurs without a loss of muscle mass or strength ( 32 ), suggesting a metabolic deficit. As exercise training increases OXCT1 activity (up to a 2-fold change) and ketone body oxidation in the skeletal muscle of rats ( 33 , 34 ), changes in OXCT1 could explain the observation that long term endurance exercise training prevents the onset of exercise intolerance in KIKO mice without restoring frataxin function ( 32 ).…”

“…Exercise intolerance in KIKO mice (at as early as 6 months of age) occurs without a loss of muscle mass or strength ( 32 ), suggesting a metabolic deficit. As exercise training increases OXCT1 activity (up to a 2-fold change) and ketone body oxidation in the skeletal muscle of rats ( 33 , 34 ), changes in OXCT1 could explain the observation that long term endurance exercise training prevents the onset of exercise intolerance in KIKO mice without restoring frataxin function ( 32 ). Our results provide a molecular mechanism that could explain the exercise intolerance in patients of FRDA and also point to the importance of exercise for FRDA patients in maintaining abilities.…”

“…Oxidative stress has been found in many cellular and animal models of FRDA as well as patient cells ( 41–44 ). Skeletal muscle of KIKO mice also undergoes oxidative stress as evidenced by increased 4-hydroxynonenal, which is ameliorated by exercise training ( 32 ). OXCT1 reduction thus might be one factor contributing to disease progression in FRDA.…”

In vivo assessment of OXPHOS capacity using 3 T CrCEST MRI in Friedreich’s ataxia

“…Future studies including more detailed assessments of exercise capacity and usual physical activity could add to our understanding. Although there is anecdotal evidence that exercise may be therapeutic in FRDA, the potential benefits of exercise in FRDA for muscle remain the focus of investigation [27].…”

Cardiovascular Research in Friedreich Ataxia

“…As noted, mitochondria within FRDA cardiomyocytes are abnormal, but it is unknown why mitophagy programs do not remove the damaged mitochondria 127 and whether this would represent a therapeutic target either by pharmaceutical or programmed exercise approaches as demonstrated by endurance training in the KIKO mice. 128 Studies on mitophagy programs using Caenorhabditis elegans and Drosophila FRDA models suggest this may be an important pathway for extension of cells’ life span. 129 , 130 Because mitochondrial expansion within the cardiomyocyte appears to be the predominant reason for cardiac hypertrophy in FRDA, 17 , 20 and most likely the cause of cardiomyocyte death, it is important to understand signaling between nucleus and mitochondria that results in this expansion.…”